Nanomaterials with enzyme-like properties (aka nanozymes) combine low cost, stability, and the unique physicochemical properties of nanomaterials with rational design of catalysts that can overcome intrinsic limitations of natural enzymes. While the vast majority of reported nanozymes exhibit oxidoreductase activity, the nanomaterials with other types of enzymatic activity remain largely unexplored. Considering that protease enzymes account for nearly 60% of the industrial market in the world, and have found applications in a number of industrial, biotechnological and scientific areas, engineered materials that mimic protease activity but are cheaper, recyclable, and more robust are of great interest. Proteases are also widely used in the field of proteomics, which after the Human Genome Project, became a rapidly growing field aiming to extract fundamental knowledge about proteins structure and function. Such information is essential for the discovery of new protein markers for disease diagnostics. Here, we propose to develop highly reactive and selective nanozymes, towards hydrolysis of protein peptide bonds, based on multifunctional hybrid composites of metal-organic frameworks (MOFs), downsized to the nanoscale (nano-MOFs). The potential of the most promising nanozymes in proteomics applications will be evaluated for the detection of protein isoforms and post-translational modifications (PTMs), which have been linked to a number of different diseases.